Boolean Networks as Predictive Models of Emergent Biological Behaviors

Interacting biological systems at all organizational levels display emergent behavior. Modeling these systems is made challenging by the number and variety of biological components and interactions (from molecules in gene regulatory networks to species in ecological networks) and the often-incomplete state of system knowledge (e.g., the unknown values of kinetic parameters for biochemical reactions). Boolean networks have emerged as a powerful tool for modeling these systems. We provide a methodological overview of Boolean network models of biological systems. After a brief introduction, we describe the process of building, analyzing, and validating a Boolean model. We then present the use of the model to make predictions about the system's response to perturbations and about how to control (or at least influence) its behavior. We emphasize the interplay between structural and dynamical properties of Boolean networks and illustrate them in three case studies from disparate levels of biological organization.Comment: Review, to appear in the Cambridge Elements serie

Autophagy induction regulates influenza virus replication in a time-dependent manner

Autophagy plays a key role in host defence responses against microbial infections by promoting degradation of pathogens and participating in acquired immunity. The interaction between autophagy and viruses is complex, and this pathway is hijacked by several viruses. Influenza virus (IV) interferes with autophagy through its replication and increases the accumulation of autophagosomes by blocking lysosome fusion. Thus, autophagy could be an effective area for antiviral research.Methodology. In this study, we evaluated the effect of autophagy on IV replication. Two cell lines were transfected with Beclin-1 expression plasmid before (prophylactic approach) and after (therapeutic approach) IV inoculation.Results/Key findings. Beclin-1 overexpression in the cells infected by virus induced autophagy to 26 %. The log10haemagglutinin titre and TCID50 (tissue culture infective dose giving 50 % infection) of replicating virus were measured at 24 and 48 h post-infection. In the prophylactic approach, the virus titre was enhanced significantly at 24 h post-infection (P≤0.01), but it was not significantly different from the control at 48 h post-infection. In contrast, the therapeutic approach of autophagy induction inhibited the virus replication at 24 and 48 h post-infection. Additionally, we showed that inhibition of autophagy using 3-methyladenine reduced viral replication. Conclusion. This study revealed that the virus (H1N1) titre was controlled in a time-dependent manner following autophagy induction in host cells. Manipulation of autophagy during the IV life cycle can be targeted both for antiviral aims and for increasing viral yield for virus production

Micromorphological, anatomical and molecular study of Hedera species (Araliaceae) in Iran

Hedera, with 12 extant species, is a genus of evergreen climbers native to Europe, north Africa, and south Asia. In this study, the micromorphological, anatomical structure and molecular evidences of 11 populations from two species of Hedera (H. helix and H. pastuchovii) have been considered to evaluate the relationships in Hedera. In total, seven quantitative and qualitative characters of pollen were selected and measured. Based on this study, the anticlinal wall and surface sculpturing of seed support for separation of two species of Hedera. Micromorphology of epidermis illustrated two types of epidermal cells: puzzle-shaped and polygonal cells. Using nuclear (nrDNA ITS) marker, we reconstructed phylogenetic relationships within two species of Hedera. This data set was analyzed by phylogenetic methods including Bayesian inference, maximum likelihood, and maximum parsimony. In phylogenetic analyses, all members of two species formed a well-supported clade (PP = 1; ML/BS = 100/100) and divided into two major clades (A and B). Neighbor Net diagram demonstrated separation of the studied populations. The results showed that these taxa differ in taxonomically important micromorphological, anatomical and molecular characteristics and these data provide reliable evidence for separation of these two species

An Anatomical, Micro-Morphological, and Ecological Study of Acantholimon cymosum (Plumbaginaceae) Endemic to Iran

The species Acantholimon cymosum with the Persian name Gypsophil Kolah Mirhasan or Cyme Kolah Mirhasan is endemic to Iran and has a limited distribution in the gypsum soils of the west and northwest of Semnan. A sampling of soil and plants, as well as a collection of ecological data, were done in the west in order to know the adaptability of A. cymosum species. Sulfate crystals were observed in the form of idioblasts in the parenchyma of the cortex, leaves, and stems. Calcium sulfate, altitude, and soil texture factors had a positive effect, but soil salinity and Calcium carbonate factors had a negative effect on the distribution of A. cymosum.IntroductionGypsum soils are one of the most widespread unusual beds in the world (Kayabas, 2020). The gypsum habitats of Iran are important reserves of biodiversity containing exclusive and rare species. However, the exclusivity of plants is often related to morphological, anatomical, and ecological adaptations (Bolukbasi et al., 2016). The species that grow in gypsum soils have different morphological characteristics. The species Bunge Acantholimon cymosum is exclusive to Iran and has been reported in the gypsum soils of the west and northwest of Semnan and Tehran (Assadi, 2005; Rechinger, 1974). The purpose of this study is to investigate the ecological conditions of A. cymosum in the gypsum areas of the west of Semnan and to analyze the relationship between environmental factors and gypsum soils with morphological, anatomical, and micro-morphological features. This research is the first comprehensive study on this exclusive species. Materials and MethodsThe area under study is located in the northern parts of Iran's famous desert called Dasht Kavir between three regions in the west of Semnan. In this regard, maps of the habitats of A. cymosum species in Iran and Semnan were prepared. A sampling of soil and plants, as well as a collection of ecological data, were done in the west of Semnan with an area of 32000 hectares from 55 stations with a distance of 500 meters from each other in order to know the adaptability of A. cymosum species. Also, the contents of gypsum, calcium (Ca), potassium (K), sodium (Na), magnesium (Mg), and calcium carbonate (CaCO3) were measured by standard methods. Spearman's correlation coefficient was used between descriptive variables, and ordination analyses were performed to investigate ecological relationships and soil and topography factors. Funding cymosum species is an exclusive species of Iran. This perennial plant has cushion-shaped bushes with an average diameter of 30 cm, dull green color, white spots or dots, numerous stems with almost long branches, and prickly leaves. The leaves are three-sided, hard, pointed, and rough. The apex is ovate-lanceolate and raised. The inflorescence is cyme, the flowers are 5, continuous and white. Examining the anatomical structure of the leaf blade and inflorescence stem sections of A. cymosum species showed that this species has thick sclerenchyma tissue around the wood and phloem vessels and calcium sulfate crystals in the form of idioblasts in the parenchyma of the leaf and inflorescence stem. The anatomical features of the leaf indicate the existence of dry structures. Due to various factors including the subtropical climate in summer and low rainfall in the central and southern parts, Semnan is a dry region with very little rainfall. The results of the analysis of the environmental factors of the A. cymosum habitats in the study area showed that the average height where this species was found was about 1600 meters above sea level.The soil texture in the areas where this species grows is often with a high percentage of sand (73% on average). The average pH and EC of the soil are 7.58 and 2.62, respectively. The average amount of lime in the vegetative soils of the species is 8% and the amount of gypsum in the vegetative soils of the species is 15%. The average species density was 0.12 m2, species abundance was 65%, and A. cymosum species cover was 23%. Results and Conclusion The term eco-morphological traits and structural characteristics have been used to name the traits of organisms that have a specific adaptive role with environmental conditions (Loidi, 2018). Many plants of specific ecosystems such as chalk and serpentine soils have found micro-morphological adaptations. Escudero and colleagues (2015) pointed out that chalks find certain adaptations in their morphological and ecological features. One of the adaptations found in this study is the presence of crystals in the hairs of the leaves. Previous studies identified gypsum crystals and calcium oxalate inside the leaf cells of gypsum plants (Palacio et al., 2014). Accumulation of gypsum inside the cell vacuole has been proposed as a detoxification strategy for gypsum native species. Although intracellular crystals were not observed in this study, the occurrence of crystals in hairs can also serve as a potential solution for detoxification. In the gypsum regions where this species grows, the dry season is very long and the intensity of drought is high. In order to prevent or reduce water loss during the dry period, plants such as A. cymosum show morphological and anatomical adaptations of their vegetative structure. The results of this study show that A. cymosum has thickened cortex, thickened leaf hairs, increased freshness (with subsequent increase in water accumulation), and a well-developed root system, all of which can be exemplified by a dry rhizome structure. Ecological factors such as soil and climate factors play an important role in the adaptation of this species. Also, a good association was observed between gypsum species in the west of Semnan, and especially between two species, A. cymosum and Astragalus semnanensis. Altitude factors, calcium sulfate, and soil sand texture have a positive effect and soil salinity and lime have a negative effect on the distribution of A. cymosum

Predicting cascading extinctions and efficient restoration strategies in plant–pollinator networks via generalized positive feedback loops

Abstract The extinction of a species in a plant–pollinator mutualistic community can cause cascading effects and lead to major biodiversity loss. The ecologically important task of predicting the severity of the cascading effects is made challenging by the complex network of interactions among the species. In this work, we analyze an ensemble of models of communities of plant and pollinator species. These models describe the mutualistic inter-species interactions by Boolean threshold functions. We show that identifying generalized positive feedback loops can help pinpoint the species whose extinction leads to catastrophic and substantial damage to the whole community. We compare these results with the damage percentage caused by the loss of species identified as important by previously studied structural measures and show that positive feedback loops and the information gained from them can identify certain crucial species that the other measures fail to find. We also suggest mitigation measures for two specific purposes: (1) prevent the damage to the community by protecting a subset of the species, and (2) restore the community after the damage by restoring a subset of species. Our analyses indicate that the generalized positive feedback loops predict the most efficient strategies to achieve these purposes. The correct identification of species in each category has important implications for conservation efforts and developing community management strategies

Incorporation of graphene quantum dots, iron, and doxorubicin in/on ferritin nanocages for bimodal imaging and drug delivery

Graphene quantum dots (GQDs) have been emerging as next‐generation bioimaging agents because of their intrinsic strong fluorescence, photostability, aqueous stability, biocompatibility, and facile synthesis. In this work, GQDs are encapsulated in ferritin protein nanocages to develop multi‐functional nanoplatforms toward multi‐modal imaging and cancer therapy. Encapsulation of ultra‐small GQDs is expected to reduce their quick excretion from the body and increase their bioimaging efficiency. To expand the functionality of protein nanocages as multi‐modal imaging nanoprobes capable of both fluorescence and magnetic resonance imaging (MRI), GQDs and iron are encapsulated inside the core of AfFtn‐AA (an engineered ferritin nanocage derived from the archaeon Archaeoglobus fulgidus ). The co‐encapsulation is achieved through an iron‐mediated, self‐assembly of ferritin dimers resulting in the formation of GQD–iron complex in the ferritin nanocages ((GQDs/Fe)AA). The (GQDs/Fe)AA shows high relaxivities in MRI and pH‐sensitive fluorescence with strong fluorescence at low pH values and on MDA‐MB‐231 cells. As an imaging agent and a drug nanocarrier, (GQDs/Fe)AA exhibits negligible cytotoxicity on the cells and a high loading capacity (35%) of doxorubicin. Taken together, the (GQDs/Fe)AA shows promising applications in cancer diagnosis and therapy as a pH‐responsive fluorophore, MRI agent, and drug nanocarrier.Accepted versio

Targeting graphene quantum dots to epidermal growth factor receptor for delivery of cisplatin and cellular imaging

The unique properties of graphene quantum dots (GQDs) which include high loading capacity, excellent physiological stability, strong photoluminescence, biocompatibility, and facile production make them attractive nanomaterials for biomedical applications. In this work, GQDs have been explored as dual-functional targeted drug carriers and cellular bioimaging agents. The GQDs were conjugated to single chain variable fragment of antibody (scFv), which had been engineered with high affinity (B10) to epidermal growth factor receptor (EGFR), via amide covalent linkages (GQDs-scFvB10). The morphology and surface modification of GQDs were characterized by HRTEM, SDS-PAGE, FT-IR, UV-vis and fluorescence spectroscopies. Western blot analysis along with the confocal imaging of EGFR-overexpressing breast cancer cells (MDA-MB-231) demonstrated the targeting functionality of scFvB10 after conjugation to the GQDs, as well as the potential application of GQDs-scFvB10 in targeted bioimaging. The surface of targeted GQDs had a high cisplatin (CDDP) loading capacity of 50% and a pH-dependent release with slower release rate at neutral conditions, which can reduce the commonly observed systemic toxicity of CDDP. The targeted CDDP-loaded nanocarriers ((CDDP)GQDs-scFvB10) exhibited significantly higher toxicity on MDA-MB-231 cells compared to non-targeted ones suggesting their efficient uptake through EGFR. In contrast, cells with saturated EGFR showed lower uptake and cytotoxic effect of (CDDP)GQDs-scFvB10, demonstrating selectivity of the nanocarriers towards EGFR-overexpressing cells. The scFvB10-functionalized GQD is a promising platform for targeted cellular imaging and delivery of CDDP through interactions with EGFRs.This work was funded partially by NTU-Northwestern Institute for Nanomedicine at Nanyang Technological University, Singapore. The authors thank Arun Kumar Prabhakar for his assistance with the initial GQDs preparation, Barindra Sana and Valerie Loh for the reconstruction of the plasmid containing scFvB10 gene

Dose-Dense Epirubicin and Cyclophosphamide Followed by Docetaxel as Adjuvant Chemotherapy in Node-Positive Breast Cancer

Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement particularly in node-positive patients, but optimal dose and schedule remain undetermined. Objectives. This study aimed to assess the feasibility of dose-dense epirubicin and cyclophosphamide followed by docetaxel in node-positive breast cancer. Methods. All Patients first received 4 cycles of epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) at 2-week interval then followed by docetaxel (100 mg/m2) at 2-week interval for 4 cycles, with daily Pegfilgrastim (G-CSF) that was administered in all patients on days 3–10 after each cycle of epirubicin and cyclophosphamide infusion. Results. Fifty-eight patients with axillary lymph node-positive breast cancer were enrolled in the study, of whom 42 (72.4%) completed the regimen. There were two toxicity-related deaths, one patient due to grade 4 febrile neutropenia and the other due to congestive heart failure. Grade 3/4 neutropenia and febrile neutropenia were 13.8% and 5.1%. The most common grade 3/4 nonhematological complications were as follows: skin-nail disorders (48.3%), hand-foot syndrome (34.4%), paresthesia (38%), arthralgia (27.5%), and paresis (24.1%). Conclusions. Dose-dense epirubicin and cyclophosphamide followed by docetaxel with G-CSF support are not feasible, and it is not recommended for further investigation